LIF expression is induced in Mller cells in response to photoreceptor stress caused by inherited mutations. Inhibiting the LIF receptor with antagonists, or knocking out the co-receptor gp130, or the signaling target STAT3 in photoreceptors, accelerates degeneration. These results show that induced LIF delays the onset and rate of retinal degeneration. We have also shown that expression of LIF decreases significantly during the time of rapid photoreceptor degeneration, and our published studies show that we can dramatically delay inherited degeneration by keeping LIF levels elevated. These results show that progression of disease is regulated by expression of LIF in Mller cells. Understanding both the induction of LIF early in disease and its suppressed expression later in disease is necessary to understand one mechanism that can determine the age of onset and rate of retinal degeneration. Understanding the regulation of LIF would also lead to the identification of potential targets that can be manipulated to promote neuronal survival by inducing and maintaining LIF expression. The goal of this project is to determine both the mechanism for induced LIF expression and the mechanism for reduction of expression that coincides with rapid degeneration. The proposal will determine the role of three receptor-signaling pathways that can coordinate to either induce or maintain LIF expression, and will determine the role to the LIF cis-acting elements in suppressing LIF expression